1. Field of the Invention
This invention is in the field of pharmaceutical agents which act as leukotriene D.sub.4 (LTD.sub.4) antagonists and includes embodiments which act as leukotriene B.sub.4 (LTB.sub.4) antagonists.
2. Prior Art
The prior art generally describes LTD.sub.4 antagonists as anti-allergy compounds and LTB.sub.4 antagonists as anti-inflammatory agents.
Leukotriene D.sub.4 and C.sub.4 (LTD.sub.4 /LTC.sub.4) and leukotriene B.sub.4 (LTB.sub.4) are products of the arachidonic acid metabolic pathway. LTD.sub.4 and LTC.sub.4 are associated with smooth muscle contraction and contract guinea pig ileum, human and guinea pig bronchi and human pulmonary artery and vein. LTB.sub.4 is associated with neutrophil stimulation and is characterized by chemotaxis, aggregation and degranulation. LTB.sub.4 is believed to be an important mediator of inflammation. High levels of LTB.sub.4 are detected in rheumatoid arthritis, gout, psoriasis, and inflammatory bowel disease. Thus antagonists of LTB.sub.4 are useful in the therapy of such diseases.
Dioxolane-2-carboxylic acids of the formula ##STR2## where R.sub.1 and R.sub.2 are the same or different H, halogen, alkyl, or alkoxy;
R.sub.3 is H, alkyl, aryl or alkyl optionally substituted by halogen, lower alkyl, or lower alkoxy; PA0 X is --CH.sub.2 --, --OCH.sub.2 -- where the O is joined to the phenyl; PA0 n is 0-3, are taught as sedatives or choleretic agents in French Pat. No. 1,445,013. PA0 X, Y, and Z are each independently O or S with S optionally oxidized to S.dbd.O; PA0 Alk is alkylene or hydroxyalkylene containing 1-6 carbon atoms; PA0 R.sub.1 is hydrogen or lower alkyl; PA0 n is 0 to 5; PA0 R.sub.2 is hydrogen, lower alkyl, cycloalkyl, --(CH.sub.2).sub.n --CO.sub.2 R.sub.1, phenyl, phenyl substituted with halo, lower alkyl or lower alkoxy; and PA0 Ar is 5,6,7,8-tetrahydro-1-naphthalenyl, phenyl, or phenyl substituted with lower alkyl, hydroxy, lower alkoxy, or lower alkanoyl.